CN114702431B - Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane - Google Patents
Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane Download PDFInfo
- Publication number
- CN114702431B CN114702431B CN202210504202.4A CN202210504202A CN114702431B CN 114702431 B CN114702431 B CN 114702431B CN 202210504202 A CN202210504202 A CN 202210504202A CN 114702431 B CN114702431 B CN 114702431B
- Authority
- CN
- China
- Prior art keywords
- pressure
- reaction kettle
- compound
- azabicyclo
- hexane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, which comprises the following steps: preparing the caronic anhydride by adopting cis-caronic dicarboxylic acid; adding the caronic anhydride into a high-pressure reaction kettle, simultaneously injecting ammonia into the high-pressure reaction kettle, and sealing the high-pressure reaction kettle; heating and stirring the high-pressure reaction kettle to reach the temperature and pressure of supercritical ammonia, preserving heat and pressure for 120-150 min, cooling the high-pressure reaction kettle to 60-70 ℃, adding hot water, cooling, stirring, crystallizing for 1-2 h, filtering, washing and drying to obtain a compound A; reducing the compound A to obtain 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane; according to the invention, ammonia is subjected to ammonolysis reaction on the caronic anhydride by forming supercritical ammonia in a supercritical state, so that other solvents are avoided being added, the ammonolysis effect can be improved, and the yield of the prepared product is higher.
Description
Technical Field
The invention relates to the technical field of preparation of medical intermediates, and relates to a preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
Background
6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is an important pharmaceutical intermediate, which is an important raw material used in the synthesis of many medicaments such as the hepatitis C protease inhibitor boscalid (Boceprevir) and the oral medicament (PF-07321332) for treating novel coronaviruses, and is widely applied to other organic synthesis fields.
In the prior art, WO2008082508 reports a method for synthesizing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane. Lithium aluminum hydride is used as a reducing agent, and then benzyl is removed by hydrogenation to prepare 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane. WO2007075790 reports another method for the synthesis of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane. Aluminum lithium tetrahydroide is also used for reduction, and HCl gas is introduced at-23 to-20 ℃ to form salt, but the purity of the final product is not mentioned in the literature. Meanwhile, the yield of the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane obtained by the preparation method in the prior art is generally not high.
Disclosure of Invention
It is an object of the present invention to address at least the above problems and/or disadvantages and to provide at least the advantages described below.
To achieve these objects and other advantages and in accordance with the purpose of the invention, there is provided a method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, comprising the steps of:
step one, preparing the caronic anhydride by adopting cis-caronic dicarboxylic acid;
step two, adding the caronic anhydride into a high-pressure reaction kettle, simultaneously injecting ammonia into the high-pressure reaction kettle, and sealing the high-pressure reaction kettle; heating and stirring the high-pressure reaction kettle to reach the temperature and pressure of supercritical ammonia, preserving heat and pressure for 120-150 min, cooling the high-pressure reaction kettle to 60-70 ℃, adding hot water, cooling, stirring, crystallizing for 1-2 h, filtering, washing and drying to obtain a compound A;
step three, reducing the compound A to obtain 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane;
the structural formula of the compound A is as follows:
the structural formula of the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is as follows:
preferably, the process in the first step is as follows: adding cis-calico dicarboxylic acid and acetic anhydride into a supercritical carbon dioxide reactor, introducing carbon dioxide, stirring and reacting for 60-90 min at the temperature of 35-40 ℃ and the pressure of 10-15 MPa, decompressing, evaporating solvent, adding methyl tertiary butyl ether and petroleum ether at the temperature of 55-65 ℃, cooling to 0-10 ℃, stirring and crystallizing, filtering and drying to obtain the calico anhydride.
Preferably, the mass ratio of the cis-calixarene dicarboxylic acid to the acetic anhydride is 2-5:6-8.
Preferably, in the second step, the molar ratio of the caronic anhydride to the ammonia gas is 1:1-10.
Preferably, the supercritical ammonia condition has a temperature of 140-165 ℃ and a pressure of 5-25 MPa.
Preferably, in the second step, the temperature of the hot water is 50-60 ℃, and the temperature is reduced to 10-15 ℃.
Preferably, the process in the third step is as follows: at room temperature, adding the compound A into toluene, cooling to 0 ℃, dropwise adding lithium aluminum tetrahydrofuran solution, heating a reaction system to 40-50 ℃ after dropwise adding, reacting for 2-4 hours, cooling to room temperature, dropwise adding dilute sodium hydroxide solution, quenching, adding water, layering, washing the water phase with ethyl acetate, merging the organic phases, drying, concentrating the filtrate under reduced pressure to obtain a light yellow liquid compound, and rectifying under reduced pressure to obtain the compound, namely 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
The invention at least comprises the following beneficial effects: according to the invention, ammonia is subjected to ammonolysis reaction on the caronic anhydride by forming supercritical ammonia in a supercritical state, so that other solvents are avoided being added, the ammonolysis effect can be improved, and the yield of the prepared product is higher.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
The specific embodiment is as follows:
the present invention is described in further detail below with reference to examples to enable those skilled in the art to practice the same by referring to the description.
It will be understood that terms, such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
Example 1:
a method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, comprising the following steps:
adding 98.6g of cis-calico dicarboxylic acid and 127.46g of acetic anhydride into a supercritical carbon dioxide reactor, introducing carbon dioxide, stirring at 38 ℃ and under the pressure of 12MPa for reacting for 60min, decompressing, distilling out solvent, adding 200mL of methyl tertiary butyl ether and 300mL of petroleum ether at 60 ℃, cooling to 4 ℃, stirring for crystallization, filtering, and drying at 35 ℃ to obtain the calico anhydride (yield 87%);
step two, adding 66g of caronic anhydride into a high-pressure reaction kettle, simultaneously injecting ammonia gas into the high-pressure reaction kettle (the molar ratio of the caronic anhydride to the ammonia gas is 1:3), and sealing the high-pressure reaction kettle; heating and stirring the high-pressure reaction kettle to reach the temperature of 145 ℃ and the pressure of 12MPa under the supercritical ammonia condition, preserving heat and pressure for 120min, cooling the high-pressure reaction kettle to 70 ℃, decompressing, adding hot water at 60 ℃, cooling, stirring and crystallizing for 2h, filtering, washing with ice water, and drying at 45 ℃ to obtain a compound A (yield 92%);
the structural formula of the compound A is as follows:
step three, adding 22g of compound A and 280mL of tetrahydrofuran into a three-necked flask at room temperature, cooling to 0 ℃, dropwise adding 350mL of 1M lithium aluminum tetrahydrofuran solution, heating the reaction system to 45 ℃ for reaction for 3 hours after the dropwise adding is finished, cooling to room temperature, dropwise adding dilute sodium hydroxide solution for quenching, adding 50mL of water, layering, washing the water phase with ethyl acetate (100 mL multiplied by 2), merging organic phases and anhydrous Na 2 SO 4 Drying, concentrating the filtrate under reduced pressure to obtain pale yellow liquid compound, and rectifying under reduced pressure to obtain the compound, namely 6, 6-dimethyl-3-azabicyclo [3.1.0]]Hexane (89% yield);
the structural formula of the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is as follows:
example 2:
a method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, comprising the following steps:
adding 98.6g of cis-calico dicarboxylic acid and 127.46g of acetic anhydride into a supercritical carbon dioxide reactor, introducing carbon dioxide, stirring at 40 ℃ and 15MPa for reacting for 60min, decompressing, distilling out solvent, adding 200mL of methyl tertiary butyl ether and 300mL of petroleum ether at 60 ℃, cooling to 4 ℃, stirring for crystallization, filtering, and drying at 35 ℃ to obtain the calico anhydride (yield 88%); the reaction is carried out in supercritical carbon dioxide, so that the addition of an additional solvent can be avoided, the preparation effect of the anhydride can be improved, the reaction is more thorough, and the yield of the prepared product is higher;
step two, adding 66g of caronic anhydride into a high-pressure reaction kettle, simultaneously injecting ammonia gas into the high-pressure reaction kettle (the molar ratio of the caronic anhydride to the ammonia gas is 1:3), and sealing the high-pressure reaction kettle; heating and stirring the high-pressure reaction kettle to reach the temperature of 150 ℃ and the pressure of 18MPa under the supercritical ammonia condition, preserving heat and pressure for 120min, cooling the high-pressure reaction kettle to 70 ℃, decompressing, adding hot water at 60 ℃, cooling, stirring and crystallizing for 2h, filtering, washing with ice water, and drying at 45 ℃ to obtain a compound A (yield 91%);
the structural formula of the compound A is as follows:
step three, adding 22g of compound A and 280mL of tetrahydrofuran into a three-necked flask at room temperature, cooling to 0 ℃, dropwise adding 350mL of 1M lithium aluminum tetrahydrofuran solution, heating the reaction system to 45 ℃ for reaction for 3 hours after the dropwise adding is finished, cooling to room temperature, dropwise adding dilute sodium hydroxide solution for quenching, adding 50mL of water, layering, washing the water phase with ethyl acetate (100 mL multiplied by 2), merging organic phases and anhydrous Na 2 SO 4 Drying, concentrating the filtrate under reduced pressure to obtain pale yellow liquid compound, and rectifying under reduced pressure to obtain the compound, namely 6, 6-dimethyl-3-azabicyclo [3.1.0]]Hexane (yield 90%); the 6, 6-dimethyl-3-azabicyclo [3.1.0]The structural formula of hexane is:
comparative example 1:
a method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, comprising the following steps:
adding 98.6g of cis-calico dicarboxylic acid and 127.46g of acetic anhydride into a three-necked flask, stirring at room temperature for reacting for 60min, evaporating out a solvent, adding 200mL of methyl tertiary butyl ether and 300mL of petroleum ether at 60 ℃, cooling to 4 ℃, stirring for crystallization, filtering, and drying at 35 ℃ to obtain the calico anhydride (yield 65%);
step two, adding 66g of caronic anhydride into a high-pressure reaction kettle, simultaneously injecting ammonia gas into the high-pressure reaction kettle (the molar ratio of the caronic anhydride to the ammonia gas is 1:3), and sealing the high-pressure reaction kettle; stirring the high-pressure reaction kettle at room temperature for 120min, adding hot water at 60 ℃, cooling, stirring, crystallizing for 2h, filtering, washing with ice water, and drying at 45 ℃ to obtain a compound A (yield 70%);
step three, adding 22g of compound A and 280mL of tetrahydrofuran into a three-necked flask at room temperature, cooling to 0 ℃, dropwise adding 350mL of 1M lithium aluminum tetrahydrofuran solution, heating the reaction system to 45 ℃ for reaction for 3 hours after the dropwise adding is finished, cooling to room temperature, dropwise adding dilute sodium hydroxide solution for quenching, adding 50mL of water, layering, washing the water phase with ethyl acetate (100 mL multiplied by 2), merging organic phases and anhydrous Na 2 SO 4 Drying, concentrating the filtrate under reduced pressure to obtain pale yellow liquid compound, and rectifying under reduced pressure to obtain the compound, namely 6, 6-dimethyl-3-azabicyclo [3.1.0]]Hexane (yield 78%). Comparative example 1 does not employ supercritical carbon dioxide and supercritical ammonia to react, resulting in lower yields of the product and, due to possible problems of incomplete reaction and impure product, 6-dimethyl-3-azabicyclo [3.1.0] as the final product]The yield of hexane is significantly reduced.
Although embodiments of the present invention have been disclosed above, it is not limited to the details and embodiments shown, it is well suited to various fields of use for which the invention is suited, and further modifications may be readily made by one skilled in the art, and the invention is therefore not to be limited to the particular details and examples shown and described herein, without departing from the general concepts defined by the claims and the equivalents thereof.
Claims (1)
1. A method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, comprising the steps of:
adding cis-calico dicarboxylic acid and acetic anhydride into a supercritical carbon dioxide reactor, introducing carbon dioxide, stirring and reacting for 60-90 min at the temperature of 35-40 ℃ and the pressure of 10-15 MPa, decompressing, evaporating out solvent, adding methyl tertiary butyl ether and petroleum ether at the temperature of 55-65 ℃, cooling to 0-10 ℃, stirring and crystallizing, filtering and drying to obtain the calico anhydride; the mass ratio of the cis-calico dicarboxylic acid to the acetic anhydride is 2-5:6-8;
step two, adding the caronic anhydride into a high-pressure reaction kettle, simultaneously injecting ammonia into the high-pressure reaction kettle, and sealing the high-pressure reaction kettle; heating and stirring the high-pressure reaction kettle to reach the temperature and pressure of supercritical ammonia conditions, preserving heat and pressure for 120-150 min, cooling the high-pressure reaction kettle to 60-70 ℃, adding hot water, cooling, stirring, crystallizing for 1-2 h, filtering, washing and drying to obtain a compound A; in the second step, the molar ratio of the carbowax to the ammonia is 1:1-10; the temperature of the supercritical ammonia is 140-165 ℃ and the pressure is 5-25 MPa;
step three, reducing the compound A to obtain 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane;
the structural formula of the compound A is as follows:
the structural formula of the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is as follows:
in the second step, the temperature of hot water is 50-60 ℃, and the temperature is reduced to 10-15 ℃; the process in the third step is as follows: at room temperature, adding the compound A into toluene, cooling to 0 ℃, dropwise adding a lithium aluminum tetrahydrofuran solution, heating a reaction system to 40-50 ℃ after the dropwise adding is completed to react for 2-4 hours, cooling to room temperature, dropwise adding a dilute sodium hydroxide solution to quench, adding water, layering, washing the water phase with ethyl acetate, merging the organic phases, drying, concentrating the filtrate under reduced pressure to obtain a light yellow liquid compound, and rectifying under reduced pressure to obtain the compound, namely 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210504202.4A CN114702431B (en) | 2022-05-10 | 2022-05-10 | Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210504202.4A CN114702431B (en) | 2022-05-10 | 2022-05-10 | Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114702431A CN114702431A (en) | 2022-07-05 |
| CN114702431B true CN114702431B (en) | 2023-06-23 |
Family
ID=82177518
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210504202.4A Active CN114702431B (en) | 2022-05-10 | 2022-05-10 | Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114702431B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115108962B (en) * | 2022-08-01 | 2024-03-19 | 上海巽田科技股份有限公司 | Method for continuously synthesizing azabicyclo compound |
| CN115232059B (en) * | 2022-08-01 | 2023-11-21 | 上海巽田科技股份有限公司 | Synthesis method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
| CN115197119B (en) * | 2022-09-01 | 2024-01-16 | 江苏科本药业有限公司 | Preparation method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2, 4-dione |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101020680A (en) * | 2006-05-17 | 2007-08-22 | 沈阳感光化工研究院 | Synthesis process of 6,6-dimethyl-3-oxo dicyclo [3,1,0]-hexane-2,4-dione |
| CN103435532A (en) * | 2013-09-02 | 2013-12-11 | 苏州永健生物医药有限公司 | Synthetic method of boceprevir intermediate |
| CN103864672A (en) * | 2012-12-18 | 2014-06-18 | 上海迪赛诺化学制药有限公司 | Method for preparing (1S, 5S)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid alkyl ester |
| CN105330589A (en) * | 2015-11-16 | 2016-02-17 | 江苏大学 | Preparation method of boceprevir intermediate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58167581A (en) * | 1982-03-29 | 1983-10-03 | Ueno Seiyaku Oyo Kenkyusho:Kk | Production of bicyclolactone |
| CN101384551B (en) * | 2005-12-22 | 2012-08-29 | 先灵公司 | Process for the preparation of 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds and enantiomeric salts thereof |
| CN102952011B (en) * | 2011-08-24 | 2015-02-18 | 南通雅本化学有限公司 | New synthetic method of carane aldehyde acid lactone |
| CN113999160B (en) * | 2021-10-21 | 2022-12-27 | 江苏省药物研究所有限公司 | Preparation method of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane |
| CN114105859B (en) * | 2022-01-27 | 2022-05-03 | 南京桦冠生物技术有限公司 | Synthetic method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
-
2022
- 2022-05-10 CN CN202210504202.4A patent/CN114702431B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101020680A (en) * | 2006-05-17 | 2007-08-22 | 沈阳感光化工研究院 | Synthesis process of 6,6-dimethyl-3-oxo dicyclo [3,1,0]-hexane-2,4-dione |
| CN103864672A (en) * | 2012-12-18 | 2014-06-18 | 上海迪赛诺化学制药有限公司 | Method for preparing (1S, 5S)-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid alkyl ester |
| CN103435532A (en) * | 2013-09-02 | 2013-12-11 | 苏州永健生物医药有限公司 | Synthetic method of boceprevir intermediate |
| CN105330589A (en) * | 2015-11-16 | 2016-02-17 | 江苏大学 | Preparation method of boceprevir intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114702431A (en) | 2022-07-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114702431B (en) | Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane | |
| CN109503462B (en) | Synthesis method of tofacitinib intermediate (3R, 4R) -N, 4-dimethyl-1-benzyl-3-piperidylamine | |
| CN112300212A (en) | Use of borane-pyridine complexes for the preparation of NK-1 receptor antagonists | |
| CN109776624B (en) | Preparation method of tribenoside | |
| CN111362886B (en) | Preparation method of posaconazole intermediate 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine | |
| US5877351A (en) | Preparation and purification process for 2- (dimethylamino) methyl!-1-(3-methoxphenyl)-cyclohexanol and its salts | |
| DE69631169T2 (en) | PREPARATION OF (S) -DECAHYDROISOCHINOLIN-3-CARBONIC ACID-T-BUTYLAMIDE | |
| AU744938B2 (en) | Purification of tramadol | |
| CN111116430B (en) | Preparation method of sodium taurate | |
| CN114835661A (en) | Industrial preparation method of a-acetyl-r-butyrolactone | |
| CN109060473B (en) | Preparation method of ambroxol hydrochloride impurity reference substance | |
| CN113354647A (en) | Ganciclovir sodium synthesis process | |
| CN112552345A (en) | Preparation method of NK-1 receptor antagonist | |
| CN112661672A (en) | Crystallization method of Boc-amino acid | |
| CN112521421A (en) | Preparation method of pharmaceutical compound | |
| CN112480172A (en) | Use of borane-pyridine complexes for the preparation of pharmaceutical compounds | |
| CN108203396B (en) | Synthesis of enkephalinase inhibitor | |
| CN106831536B (en) | Preparation method of gliclazide synthesis process | |
| CN109293524B (en) | Preparation method of high-purity diacetone acrylamide | |
| US6037494A (en) | Process for the crystallization from a linear or branched (C5-C6) alcohol or their mixtures of (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyy l)amino]-2,4,6-triiodo-1,3-benzendicarboxamide | |
| CN114751853B (en) | Process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane compounds | |
| CN113956173B (en) | Preparation method of tranexamic acid | |
| CN114940643B (en) | Synthesis method of medical hydroquinone | |
| CN116120395A (en) | Preparation method of Nemactetvir intermediate | |
| CN117263807B (en) | Dialkyl dimethyl ammonium chloride and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |